Biomedical Engineering Reference
In-Depth Information
Subsequent treatment of
with [Ir(COD)(OMe)]
2
(4mol%), dtbpy (8mol%), and
B
2
pin
2
(0.75 equiv) in THF at 80
C provided
101
in 75% yield. This C-H bond
functionalization occurred with high levels of selectivity at the C3 position, which is
consistent with previous observations for pyridine derivatives (Scheme 1.23c) [83]
and highlights the role of steric effects on regioselectivity in C-H borylation
chemistry. With the second coupling partner in hand, palladium-catalyzed Suzuki
cross-coupling between
104
100
and
101
followed by protecting group removal afforded
(
þ
)-complanadine A (
99
).
1.10. RHODIUM(I)-CATALYZED INTRAMOLECULAR
DIRECTED ALKYLATION OF sp
2
C-H BONDS
Similar to palladium-based systems, rhodium catalysts have been significantly
investigated in the context of C-C bond formation at C-H bonds due to the variety
of transformations they can perform and their general functional group tolerance [90].
The use of Rh(I) catalysis has emerged as a powerful tool for the addition of an sp
2
C-H bond across an unsaturation, leading to the formal alkylation or alkenylation of
arenes and olefins [91,92]. Typically, chelating functional groups on the substrate are
required to direct site-selective C-H bond functionalization (see Section 1.6), with
pyridine and more recently imine moieties having been exploited to this effect.
Compared to Rh(I)-catalyzed (hetero)arene C-H functionalizations, the
equivalent reactions using olefin C-H bonds are significantly less developed (see
Section 1.10). This can be attributed to two inherent challenges in these systems [90b].
First, olefin isomerization under the reaction conditions leads to product mixtures.
Moreover, carbonyl-derived chelating groups (i.e., imines) not only direct cyclorho-
dation but also activate the alkene toward competitive side reactions such as conjugate
additions. Although the latter challenge has traditionally been overcome by using
heterocycle-containing directing groups [92a], the development of new catalysts that
combine a Rh(I) precatalyst with an electron-donating phosphine ligand has enabled
the efficient use of imines as directing groups [92c-e]. With the establishment of these
more efficient catalysts for C-H functionalization, reaction temperatures can be
significantly decreased, thus minimizing the problems ensuing from olefin iso-
merization. It should also be noted that this issue is much less problematic in
intramolecular reactions.
The scope of
intermolecular
arene alkylation reactions is unfortunately very
limited with respect to the olefin coupling partner. For example, internal olefins
rapidly isomerize to terminal olefins, leading exclusively to linear substituted
products. As well, olefins with heteroatom substituents, for example, vinyl ethers,
are not tolerated in these reactions. However, these problems can be avoided by
performing the reaction in an
intramolecular
fashion, where the alkene is tethered
meta
to the directing group.
In 2005, Bergman, Ellman, and coworkers reported the total synthesis of
(
) [93], a compound of interest in the development of
a treatment for AIDS due to its ability to inhibit HIV-1 integrase [94]. The highly
functionalized dihydrobenzofuran core of this target was prepared using an
þ
)-lithospermic acid (
105
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